1. Field of the Invention
This invention relates to nitric oxide donor compounds and, more particularly, to such compounds and their pharmaceutical compositions for use in delivering nitric oxide to the apical surface of a mucosa, where the nitric oxide is released for passage across the epithelial monolayer of the mucous membrane. The invention also relates to the treatment of specific conditions and disorders in which the local delivery of nitric oxide has a salutory effect. Such conditions and disorders include, for example, pulmonary hypertension and impotence, which benefit from the invention's ability to cause local vasodilation without causing a similar vasodilation of the systemic vasculature.
2. Description of the Related Art
Pulmonary hypertension is a serious medical condition. Acute pulmonary hypertension, resulting from a deficiency of nitric oxide (NO) production in the pulmonary vasculature or from a non-NO related process, increases pulmonary capillary pressure, augments transvascular flux, and increases right ventricular afterload. Additionally, in the presence of right to left anatomic extrapulmonary shunts or intrapulmonary physiologic shunts, pulmonary hypertension may contribute to systemic desaturation. Chronic pulmonary hypertension also may induce remodeling of the pulmonary vasculature, inducing an irreversible smooth muscle hypertrophy.
In addition to being quite serious, pulmonary hypertension is frequently encountered, resulting from a number of conditions, including for example, adult respiratory distress syndrome, neonatal respiratory distress syndrome, pneumonia, asthma, bronchiolitis, chronic obstructive pulmonary disease, restrictive lung disease, near drowning, cardiopulmonary arrest, cardiopulmonary bypass, emphysema, sepsis, infection, shock, congenital heart disease and congenital diaphragmatic hernia.
Recently, NO has been shown to be a useful agent in the treatment of pulmonary hypertension when delivered in its gaseous form to the lung via an endotracheal route during mechanical ventilation. Nelin L, Moshin C, Sasidharan T, Dawson C, "The effect of inhaled nitric oxide on the pulmonary circulation of the neonatal pig," Pediatric Research 1994, 35:20-24; Etches P, Finer K, Barrington A, Graham A, Chan W, "Nitric oxide reverses acute hypoxic pulmonary hypertension in the newborn piglet," Pediatric Research 1994, 35:15-19. Although the exact mechanism by which inhaled NO dilates the pulmonary vascular bed is unknown, it is presumed that NO is distributed to distal ventilated alveolar segments, where it passes readily due to its great lipophilicity, through the epithelium into the interstitial space. From there, NO passes through the vascular adventitia and reaches the cytosol of the arteriolar vascular smooth muscle, where it interacts with iron in the heme center of guanylyl cyclase. NO binding induces a conformational change in the enzyme which permits the catalysis of GTP to cGMP, with a subsequent alteration in intracellular calcium and vascular smooth muscle relaxation. NO, which instead passes through the vascular smooth muscle and endothelium and into the vascular lumen, is believed to be inactivated by its interaction with the iron center in hemoglobin. In this manner, NO is believed to be a selective pulmonary vasodilator, since it becomes immediately ineffective in the systemic circulation. Although some recent evidence suggests that NO may circulate as a relatively stable adduct, in the form of a nitrosylated hemoglobin species, which could in theory cause systemic vasodilation, in practice, inhaled NO does not appear to have any direct effect on systemic vascular resistance.
Although inhalation of nitric oxide gas has been shown useful in the treatment of pulmonary hypertension, there are several drawbacks and limitations with this particular mode of therapy. For example, this therapy requires large gas tanks, expensive monitoring equipment, and a highly skilled technician to operate the tanks and equipment and deliver the NO gas to a patient. Therefore, this mode of treatment is generally limited to a hospital or other clinical setting and, even then, is inconvenient and relatively expensive. Given the seriousness and incidence of pulmonary hypertension, there is a great need for a more flexible, less expensive mode of treatment, in which a vasodilator such as NO may be delivered to the lung without causing undesirable systemic vasodilation.
Another NO-mediated condition is impotence, that is, the inability of a male to achieve or maintain an erection. Penile erection involves parasympathetic, neuronally mediated relaxation of the blood vessels and the trabecular meshwork of smooth muscle that constitutes the corpora cavernosa. The relaxation of the cavernous smooth muscle plays a critical role in erection, which is largely nerve-mediated by a nonadrenergic, noncholinergic (NANC) mechanism; however, endothelium-dependent cholinergic neurotransmission may also mediate penile erection. Recent studies have shown that nitric oxide (NO) is the major neuronal mediator of erection. Several in vitro studies have demonstrated that NO is responsible for the relaxation of rabbit and human corpus cavernosum smooth muscle strips. In vivo studies in rats and dogs also demonstrated that NO is the principal neurotransmitter in cavernous smooth muscle relaxation. Wang R, Domer F R, Sikka S C, Kadowitz P J, Hellstrom W J G, "Nitric oxide mediates penile erection in cats," The Journal of Urology 1994, 151:234-237. In the past, treatment options for impotence have included direct smooth muscle vasodilators such as papaverine and vasodilator prostaglandins, such as PGE.sub.2, to name a few. More recently, the NO donors s-nitrosocysteine (NO-CYS) and s-nitroso-n-acetylpenicillamine (SNAP) have been proposed for therapeutic use. Id. However, since the safety and long-term effects of NO-CYS and SNAP have yet to be studied in human clinical trials, it would be extremely beneficial to develop additional therapies.